Abstract
The various sphingosine kinase (SphK) isoenzymes (isozymes) and isoforms, key players in normal cellular physiology, are strongly implicated in cancer and other diseases. Mutations in SphKs, that may justify abnormal physiological function, have not been recorded. Nonetheless, there is a large and growing body of evidence demonstrating the contribution of gain or loss of function and the imbalance in the SphK/S1P rheostat to a plethora of pathological conditions including cancer, diabetes and inflammatory diseases. SphK is expressed as two isozymes SphK1 and SphK2, transcribed from genes located on different chromosomes and both isozymes catalyze the phosphorylation of sphingosine to S1P. Expression of each SphK isozyme produces alternately spliced isoforms. In recent years the importance of the contribution of SpK1 expression to treatment resistance in cancer has been highlighted and, additionally, differences in treatment outcome appear to also be dependent upon SphK isoform expression. This review focuses on an exciting emerging area of research involving SphKs functions, expression and subcellular localization, highlighting the complexity of targeting SphK in cancer and also comorbid diseases. This review also covers the SphK isoenzymes and isoforms from a historical perspective, from their first discovery in murine species and then in humans, their role(s) in normal cellular function and in disease processes, to advancement of SphK as an oncotarget.
Highlights
Sphingosine kinase (SphK), categorized as a bioactive lipid enzyme, is a central player in the sphingolipid rheostat [1,2,3,4,5]
Xia and colleagues first identified the oncogenic potential of SphK1 in 2000 [221], and evidence supporting a key role in neoplastic survival and growth has come from SphK1-/- mouse models showing reduced tumor size [222] and increased expression of human SphK1 (hSphK1) has been reported in many different cancer types (Table 1) [97, 223]
In particular we review how aberrant expression of the hSphK1 isoforms can confer resistance to SphK1 targeted drugs [25, 26, 102] highlighting the challenges faced in anti-SphK drug treatment in cancer therapy
Summary
Sphingosine kinase (SphK), categorized as a bioactive lipid enzyme, is a central player in the sphingolipid rheostat [1,2,3,4,5]. Xia and colleagues first identified the oncogenic potential of SphK1 in 2000 [221], and evidence supporting a key role in neoplastic survival and growth has come from SphK1-/- mouse models showing reduced tumor size [222] and increased expression of hSphK1 has been reported in many different cancer types (Table 1) [97, 223].
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